According to various reports by VisionGain, Frost and Sullivan, the WHO, and others, the worldwide market for prefilled syringes (PFS) has been growing for two decades. Prefilled syringes introduced convenience and accuracy to self-administered drugs. They are easy to handle and always ready to be used. The emergence of biotechnology is another key driver in the development of a market that achieves double-digit growth rates. For equipment manufacturers this development has implications for the future of processing syringes, in particular for the filling and closure process.
Prefilled syringes have developed from a niche product to a primary container of choice. The advantages prefilled syringes have over traditional packaging include more than ease of use. Modern prefilled syringes reduce the need for vial over-filling. With the advent of biotech drugs with high development costs, this means less waste and moreover helps eliminate the dangerous risk of dosing errors.
Whatever the speed, equipment manufacturers need to keep up with the development of the pharmaceutical market environment. There are several trends with mid- and long-term influence on processing prefilled syringes we will further explore in this article.
Trends that Influence PFS Processing
Production of prefilled syringes is a multi-step process ranging from manufacturing, siliconizing and sterilizing syringes as well as relevant plastic components to filling and closure processes, and so-called medical devices. Quality assurance and qualification are always key prerequisites to support risk minimization.
A major trend is the ongoing boom in biotechnology. Biologic drugs can help accomplish results in the human body that have been inapproachable for small molecule therapies. In this market segment, highly individual products of high quality and value are produced in small batches.
In general, these drugs are best supplied in liquid form filled in syringes. As a result, syringes themselves have been a booming market. And although it is often required, freeze-drying to improve shelf life can be perceived as the second-best solution, due to its more elaborate process.
The extent of automation in production will continue to increase, at least in highly industrialized countries, as this clearly helps leveraging product quality. And because of their potential to minimize manual interventions — the main cause for particles and germ cell entry — automatic solutions are intensely sought after. For example, the fully automatic opening of sterile syringe packaging has long been a standard requirement for new filling lines.
In-process control plays an important role for further improving the quality of prefilled syringes by helping to prevent syringes not in line with specifications from being packaged. Modern filling equipment therefore should at least open up the possibility to improve quality by providing in-process control. This applies not only to filling weight but also to other variables such as closure elements and siliconization. Regulatory requirements for the use of Process Analytical Technology (PAT) are expected to be expanded.
The primary packaging market is a dynamically developing market that requires answers to this challenge. Established manufacturers increase their production capacities, while new manufacturers enter the market. Moreover, the number of diversifications and customer-specific solutions will increase. We find the following mid- and long-term scenarios to be realistic.
Future Developments in Processing
Standardization of plastic packaging: All syringes should be able to be processed on all machines. Hence, the most important parameters should be equal, independent of the manufacturer. These parameters include materials, dimensions, and features such as the connection of tub and stretch sheet.
Optimized silicon distribution: From a PAT point of view, examination of silicon distribution should take place before filling — even more so as highly automated filling machines with flexible handling units are already able to pick predefined syringes from a nest. Thus, single syringes could be fed into a line-integrated control station easily. Formerly, syringes have only been checked as to whether they were siliconized at all. Today there are methods to examine the thickness and distribution of the silicon layer inside the syringe, as stoppering should fulfill its sliding function in autoinjection devices with minimal silicon entry. However, these methods are in a relatively early stage of development, and more data must be collected. In the long run, new coatings could become serious alternatives, with the use of plasma technology being one example.
The Equipment Manufacturer Perspective
Prefilled syringes are of special interest for equipment manufacturers in the sense that the final product is ready for medical use without any intermediate steps. As primary packaging, prefilled syringes are closer to the patient than ampoules or vials are.
Fully automatic bag and tub opening are trending in industrialized countries and beyond. Due to intense competition, the speed of development for new solutions is very high. Different solutions have been established in the market in a short period of time.
Semi-automatic processes are partly being accepted for bag opening. This does not apply to the introduction of tubs into the sterile room, in particular for zone crossing from clean room C to A. A main driver for the discussion is the electron beam sterilization tunnel for the surface decontamination of tubs. The solution is almost a standard on high performance production lines with isolators.
So why is e-beam not being used on restricted access barrier system (RABS) lines? This basic question leads to the discussion of several issues: Where exactly is the border between zones C-A? When and where should the bag be opened? The more precisely these questions can be technically answered, the more e-beam will face challenges to be successful apart from or even with the isolator.
Filling Process: Single-use in Demand
Single-use filling systems are widely discussed for filling syringes. Biologics are the main driver for this trend as well. Cleaning and validating parts of the product in processing biologic products is so expensive and time-consuming that the introduction of single-use systems makes sense. In this context, peristaltic pumps are becoming interesting again. Because peristaltic pumps do not have contact with the product that is to be filled, only the tube has to be switched. Moreover, the pharmaceutical industry often uses peristaltic pumps during drug development. Filling volumes typically vary between 50 microliters and three milliliters.
Testing Before Filling
How can the syringe be tested before it is filled with an expensive drug? Possible check parameters could be the completeness of the nest, the existence of tip closures and the identification of bent needles. In order to check syringes prior to filling, camera systems could be used. Although control systems on filling equipment have long been called for, companies disclaim their use for technical and business reasons. They were too expensive and had too much impact on the laminar flow, to name some of the reasons they gave. Yet compared to other trends discussed in this article, these systems are most likely to be implemented.
Different Closure Methods
After filling is complete, the traditional stoppering technique is vented placement. A stopper is placed inside a tube that is then inserted into the syringe. As the tube is removed from the syringe, a pin holds the stopper in place.
Driven by the biotech boom, more stoppers that incorporate coating will be used. They are often too sensitive for vented placement; an alternative stoppering technique is vacuum placement. A vacuum is pulled in each syringe, and the vacuum draws the stopper into the syringe. Vacuum placement does not compress stoppers as much as vented placement does. However, vacuum placement contains more variables and places stoppers less precisely. Furthermore, the method requires more time and decreases the syringe-filler line speed.
The market has already decided: Few new projects are being launched for bulk. Pre-sterilized syringes are prevailing. Yet it has to be kept in mind that some production lines have a very high output, whereas pre-sterilized syringes are designed for much smaller batches and disposal issues have a low ranking. Maybe in this particular field the development will change but there is no evidence yet.
Overall, the trend towards prefilled syringes is irreversible. Biotechnology will determine the development of this packaging in the future. For equipment manufacturers this implies the development of individual solutions for individual product features. It also requires a better process understanding on the basis of PAT, which means better quality and higher yield. Most of the drugs are very expensive and are often being used in medical devices (auto injectors). Disposable filling systems will increasingly be used. Given the success of pre-sterilized syringes, the industry might also start thinking about pre-sterilized vials and cylindrical ampoules. Perhaps it’s a niche product today — but tomorrow? Keep in mind that nested syringes have also once started as an “exotic product.”
Klaus Ullherr is product manager for syringes and cartridges at Robert Bosch GmbH. He is also a member of the PDA’s Interest Group on Prefilled Syringes. He can be reached at email@example.com. Mr. Ullherr gives special thanks to Dr. Bernd Sennhenn of Abbott GmbH & Co. KG, for his constant support and the interesting discussions that led to this article.